Hepsin is a type II transmembrane serine protease (TTSP) expressed on the surface of epithelial cells. The 417-amino acid protein is composed of a short N-terminal cytoplasmic domain, a transmembrane domain and a single scavenger receptor cysteine-rich domain that packs tightly against the C-terminal protease domain (Somoza et al (2003) Structure 11(9), 1123-1131). The physiologic function of hepsin is unclear. Despite its expression in the very early stages of embryogenesis (Vu et al (1997) J Biol Chem 272 (50), 31315-31320), hepsin-deficient mice were viable and developed normally (Yu et al (2000) Thromb Haemost 84(5), 865-870; Wu et al (1998) J Clin Invest 101(2), 321-326). Hepsin was found not to be essential for liver regeneration and for coagulation-related physiological functions (Id.). A recent study demonstrated that hepsin knock-out mice are hearing impaired. Guipponi et al. (2007) Am J Pathol 171:608-616. However, hepsin has been implicated in ovarian [(Tanimoto et al (1997) Cancer Res 57(14), 2884-2887); WO2001/62271] and prostate cancer. Several gene expression studies identified hepsin as one of the most highly induced genes in prostate cancer (Dhanasekaran et al (2001) Nature 412, 822-826; Luo et al (2001) Cancer Res 61(12), 4683-4688; Magee et al (2001) Cancer Res 61(15), 5692-5696; Stamey et al (2001) J Urol 166(6), 2171-2177; Stephan et al (2004) J Urol 171(1), 187-191; Welsh et al (20010) Cancer Res 61(16), 5974-5978). Hepsin RNA levels were found to be low in normal prostate and benign hyperplasia, but strongly increased in prostate carcinoma, particularly in advanced stages ((Dhanasekaran et al (2001) Nature 412, 822-826; Luo et al (2001) Cancer Res 61(12), 4683-4688; Magee et al (2001) Cancer Res 61(15), 5692-5696; Stamey et al (2001) J Urol 166(6), 2171-2177; Stephan et al (2004) J Urol 171(1), 187-191; Welsh et al (20010) Cancer Res 61(16), 5974-5978). Hepsin protein staining with a monoclonal anti-hepsin antibody showed that hepsin expression was highest at sites of bone metastasis and in late stage primary tumors (Xuan et al (2006) Cancer Res 66(7), 3611-3619), which is consistent with the finding that increased hepsin RNA levels correlated with higher Gleason grades and tumor progression ((Luo et al (2001) Cancer Res 61(12), 4683-4688; Magee et al (2001) Cancer Res 61(15), 5692-5696; Stamey et al (2001) J Urol 166(6), 2171-2177; Stephan et al (2004) J Urol 171(1), 187-191; Chen et al (2003) J Urol 169(4), 1316-1319).
Experimental evidence for a role of hepsin in prostate cancer came from a study by Klezovitch et al. (Klezovitch et al (2004) Cancer Cell 6(2), 185-195) demonstrating that in a mouse model of non-metastasizing prostate cancer, overexpression of hepsin led to primary tumor progression and metastasis. Intriguingly, hepsin overexpression was associated with basement membrane disruption (Id.) pointing towards the possibility that hepsin activity is somehow linked to the degradation of basement membrane components. In-vitro, hepsin is able to convert the latent growth factor pro-hepatocyte growth factor (pro-HGF) into its active two-chain form (HGF), which induced Met receptor signaling (Herter et al (2005) Biochem J 390 (Pt 1), 125-136; Kirchhofer et al (2005) FEBS Lett 579(9), 1945-1950; WO2006/014928). Hepsin is also able to convert pro-uPA to its active form (Moran et al, (2006) J Biol Chem. 281(41):30439-46), and to cleave lamin in vitro (Tripathi et al. (2008) J Biol Chem. 283:30576). Because the HGF/Met pathway has been implicated in invasive tumor growth and metastasis, it is possible that overexpression of hepsin activates the HGF/Met axis in prostate cancer (Herter et al (2005) Biochem J 390 (Pt 1), 125-136; Kirchhofer et al (2005) FEBS Lett 579(9), 1945-1950; WO2006/014928). Hepsin was also shown to cleave other substrates in-vitro, mainly coagulation-related proteins (Herter et al, id; Kazama et al (1995) J Biol Chem 270(1), 66-72). However, their role in tumorigenesis is not known.
It is clear that there continues to be a need for agents that have clinical attributes that are optimal for development as therapeutic agents. The invention described herein meets this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.